1,2,4-triazolo 1,5-c! pyrimidine heterocyclic analogues having antagonistic activity on adenosine A2a receptor

ABSTRACT

Disclosed are adenosine A 2a  receptor antagonists of the formula ##STR1## wherein A is pyrazole, imidazole or triazole ring; R is ##STR2## R 1  and R 2  are independently H, OH, halogen, alkoxy, alkyl, nitro, amino, CN, haloalkyl, haloalkoxy, carboxy or carboxamido; or the OH group together with one of R 1  or R 2 , or R 1  and R 2  together, form a methylenedioxy group; 
     and n is 0-4; 
     said compounds are useful in the treatment of cardiovascular, central nervous system, and respiratory diseases.

The present invention relates to compounds having antagonistic activityon adenosine A_(2a) receptors.

Adenosine is known to be an endogenous modulator of a number ofphysiological functions. At the cardiovascular system level, adenosineis a strong vasodilator and a cardiac depressor. On central nervoussystem, adenosine induces sedative, anxiolytic and antiepilepticeffects. On the respiratory system, adenosine inducesbronchoconstriction. At the kidney level, it exerts a biphasic action,inducing vasoconstriction at low concentrations and vasodilatation athigh doses. Adenosine acts as a lipolysis inhibitor on fat cells and asan antiaggregant on platelets (Stone T. W. Purine receptors and theirpharmacological roles. In: Advances in drug research. Academic PressLimited, 1989, 18, 291-429; Progress Cardiovasc. Dis. 1989, 32, 73-97;Williams M., Adenosine and Adenosine receptors. The Humana Press, 1990).

Adenosine action is mediated by the interaction with different membranespecific receptors which belong to the family of receptors coupled withG proteins.

Biochemical and pharmacological studies, together with the recentacquirements in the molecular biology field, have up to now allowed toidentify at least 4 different adenosine receptors: A₁, A_(2a), A_(2b),ed A₃ (Pharmacol. Rev., 1994, 46, 143-156).

Intense research efforts have made it possible to identify and developanalogs to adenosine able to interact as agonists with the A₁, A_(2a)and A₃ receptors (Pharmacol. Rev., 1994, 46, 143-156).

The knowledge available on the physiological role of adenosine and itsinvolvement in some pathological processes suggests that selectiveantagonists for the A_(2a) receptor can be of pharmacological interest.At the level of the central nervous system, antagonistic A_(2a)compounds could have antidepressive properties and stimulate thecognitive functions. Moreover, numerous data show that the A_(2a)receptors are present in high density in the basal ganglia of which theimportance in the control of movement is known. Hence, the hypothesisthat A_(2a) antagonists can improve motor-impairment due toneurodegenerative processes. Amongst these are included Parkinson'sdisease, senile dementia as in Alzheimer's disease and psychosis oforganic origin (Drug Dev. Res., 1993, 28, 381-385).

At a peripheral level, A_(2a) receptor antagonists could stimulate therespiratory functions and therefore have a therapeutic effect in thetreatment of bronchospasm and, more generally, asthma. Moreover, withregard to the effects at a cardiovascular or renal level, anadvantageous activity on renal flow can be envisaged and therefore thepossibility of the treatment of renal insufficiency and of variouscardiovascular disturbances.

Whilst some xanthine-structure have been known to be A₁ receptorselective antagonists (J Med. Chem., 1992, 35, 407-422), only recentlynovel xanthine (J. Med. Chem, 1993, 36, 3731-3733) and non-xanthine (PCTWO 9501356, published on Dec. 1, 1995, corresponding to Italian Patentapplication MI93A001396) Bioorg. Med. Chem. Lett, 1994, 4, 2539-2544)have been found to have high A_(2a) affinity and moderate A_(2a) vs A₁selectivity (about 50-fold).

The compounds disclosed in WO 9501356 are 1,2,4-triazolo1,5-c!pyrimidine heterocyclic analogues, on the heterocyclic ring ofwhich is present, inter alia, an aryl group, particularly phenyl orphenylalkyl, optionally substituted with halogen atoms, C_(1-C) ₄alkoxy, C₁ -C₄ alkyl, nitro, amino, cyano, C₁ -C₄ haloalkyl, C₁ -C₄haloalkoxy, carboxy, carboxamido groups.

Moreover, it has surprisingly been found that the presence of at leastone hydroxyl on the phenyl ring gives the compounds disclosed inW09501356 an increased A_(2a) selectivity.

Therefore, the present invention relates to compounds of general formulaI: ##STR3## wherein: A is a pyrazole, imidazole or triazole ring##STR4## R₁ and R₂, which are the same or different, are H, OH, halogen,C₁ -C₄ alkoxy, C₁ -C₄ alkyl, nitro, amino, cyano, C₁ -C₄ haloalkyl, C₁-C₄ haloalkoxy, carboxy, carboxamido groups; moreover the OH group,together with one of R₁ or R₂, or R₁ and R₂, can form the methylenedioxygroup --O--CH₂ --O--;

n is an integer from 0 to 4.

The invention also comprises the pharmaceutically acceptable salts ofthe compounds of general formula I.

The possible meanings of A can be represented by the followingstructural formulae: ##STR5##

Examples of C₁ -C₄ alkyl groups include methyl, ethyl, propyl,isopropyl, butyl and isobutyl.

Examples of C₁ -C₄ alkoxy groups are methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy.

Halogen atoms are fluorine, chlorine, bromine, iodine.

Examples of C₁ -C₄ groups haloalkyl are trifluoromethyl, 2-fluoroethyl,2-chloroethyl.

Examples of C₁ -C₄ haloalkoxy groups are trifluoromethoxy chloromethoxy,2-fluoroethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy.

Preferred compounds of formula I are those wherein A is pyrazolo 4,3-e!or 1,2,3-triazolo 5,4-e!.

Particularly preferred compounds of formula I are those wherein A ispyrazolo 4,3-e!, n ranges from 1 to 4 included, preferably 2 or 3, theOH group on the phenyl ring is at the para position and R₁ and R₂ arehydrogen.

A second group of particularly preferred compounds of formula I arethose wherein A is pyrazolo 4,3-e!, n is from 1 to 3, preferably 1 or 2,the OH group on the phenyl ring is at the meta position and R₁ and R₂are hydrogen.

A third group of particularly preferred compounds of formula I are thosewherein A is pyrazolo 4,3-e!, n is from 1 to 4, preferably 2 or 3, theOH group on the phenyl ring is at the para position, R₁ is methoxy,preferably at the meta position, R₂ is hydrogen.

A fourth group of particularly preferred compounds of formula I arethose wherein A is pyrazolo 4,3-e!, n is from 1 to 4, preferably 2 or 3,the OH group on the phenyl ring is at the para position, R₁ is hydroxy,preferably at the meta position, R₂ is hydrogen.

A fifth group of particularly preferred compounds of formula I are thosewherein A is 1,2,3-triazolo 5,4-e!, n is from 1 to 4, preferably 2 or 3,and the OH group on the phenyl ring can be at all the possiblepositions.

Particularly preferred are the following compounds:

5-amino-7- β-(4-hydroxy-3-methoxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-7- β-(3-hydroxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-7- β-(2-hydroxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-7- γ-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-pyrazolo4,3-e!1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-7- 4-hydroxybenzyl!-2-(2-furyl)-pyrazolo 4,3-e!-1,2,4-triazolo1,5-c!pyrimidine;

5-amino-7- β-(3,4-dihydroxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyriidine;

5-amino-8- β-(4-hydroxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-8- γ-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-8- β-(3,4-dihydroxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-8- β-(3,4-methylenedioxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-8-(4-hydroxybenzyl)-2-(2-furyl)-pyrazolo 4,3-e!-1,2,4-triazolo1,5-c!pyrimidine;

5-amino-7- β-(4-hydroxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-7- β-(4-hydroxy-3-iodo)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-7- γ-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-7- γ-(4-hydroxy-3-iodo)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-7-β-(3,4-dihydroxy)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo1,5-c!-pyrimidine;

5-amino-7-β-(3,4-methylenedioxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; m.p 210-211° C.;

5-amino-8- β-(4-hydroxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-8- γ-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-8- β-(3,4-dihydroxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-8-β-(3,4-methylenedioxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-7- β-(4-hydroxy-3-iodo)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-7-γ-(4-dihydroxy-3-iodo)-phenylpropyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo1,5-c!-pyrimidine;

5-amino-7- β-(3,4-methylenedioxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

The compounds according to the present invention are prepared with knownprocesses, in particular they are according to the processes describedin WO Application 9501356.

Since in all the intermediates for the synthesis of the compounds ofFormula I at least one OH group is present on the phenyl ring, toprotect the OH group(s), during the various synthetic steps. The finalcompounds of formula I are thus obtained by deprotecting the phenyl OHgroup(s) once the complete structure has been obtained. Protectionmethods are conventionally known, for example as described in T. W.Greene, P. G. M. Woots, Protective Groups in Organic Synthesis, J.Wiley. N.Y. 1991, 2nd Edition.

A preferred protection method is the benzylation and followingdebenzylation on Pd/C in tetrahydrofuran. Alternatively, the protectionmethod involves the use of the allyl group or, when two adjacent hydroxygroups are present, the methylendioxy group.

Therefore, another object of the present invention is a process for thepreparation of compounds of formula (I), as reported above, whichcomprises the deprotection of the phenyl hydroxy groups of the compoundsof formula (Ia) ##STR6## wherein: A is as defined in formula (I);##STR7## wherein D is a suitable protective group, preferably benzyl orallyl (or --CH₂ -- as protective group of two adjacent hydroxyl groups),R₁ and R₂, which are the same or different, are hydrogen, OD, wherein Dis as defined above, a halogen atom, C₁ -C₄ alkyl, nitro, amino, cyano,C₁ -C₄ halogen alkoxy, carboxy, carboxamido group; n is as abovedefined.

The process according to the present invention also comprises theoptional transformation of the obtained compound into a pharmaceuticallyacceptable salt.

BIOLOGICAL ACTIVITY

The pharmacological properties of the disclosed compounds were studiedin the most sensitive and suitable experimental models both in vitro andin vivo.

The compounds of general formula I have advantageous properties ofselectivity for the A_(2a) receptor compared with those described in theabove cited WO 9501356.

Adenosine A_(2a) receptor affinity was tested by means of receptorbinding techniques on bovine and rat (Sprague-Dawley strain), cerebellarcorpus striatum, which is a tissue rich in A_(2a) receptors. Compound ³H-CGS 21680 (J. Pharm. Exp. Ther. 1989, 251, 888-893) was used as theradioligand. The A₁ receptor affinity was tested with receptor bindingtechniques on bovine and rat (Sprague-Dawley strain), cerebellar cortexmembranes, which is a tissue rich in A₁ receptors. ³H-Cyclohexyl-adenosine, ³ H-CHA (Proc. Natl. Acad. Sci.--USA--1980, 77,5547-5551) was used as the radioligand. The selectivity for the A_(2a)receptor was evaluated from the comparison between the affinities forthe A₁ or A_(2a) receptor shown by each compound. A number ofexperimental data support the evidence that a marked relationship existsbetween the affinity found with binding techniques in brain tissues andthe physiological effects modulated by adenosine receptors.

A_(2a) receptors are mainly present in the vascular system and thestimulation thereof causes vasodilation. Therefore, the A_(2a)antagonistic activity of these molecules has been studied by evaluatingthe capability of inhibiting vasodilation induced by adenosine agonistsin vascular tissues such as rat aorta and bovine or porcine coronaryarteries.

These compounds were unable to antagonize negative chronotropic effectsinduced by A₁ receptor agonists when tested on isolated rat atria (Br.J. Pharmacol., 1983, 78, 207-212).

Another test to evaluate the antagonistic activity of the new compoundsis the study of platelet aggregation. In fact, adenosine or theanalogues thereof are known to inhibit platelet aggregation induced bydifferent aggregatory agents, among which ADP. Therefore, the capabilityof the novel compounds of antagonizing the inhibitory effect induced byNECA or CGS 21680 agonists was tested using rabbit platelets.

This test is particularly important as only the A_(2a) receptor ispresent on platelet cell membranes.

The in vivo activity was evaluated in Swiss mice and spontaneouslyhypertensive rats (SHR). The behavioural response to a treatment withdifferent doses of the tested compounds administered parenterally wasevaluated in the mice. In the SHR rats, the tested compounds wereadministered parenterally at increasing doses and the capability thereofof antagonizing the bradycardic and hypotensive effects induced by A₁and A_(2a) receptor agonists, respectively, was measured.

A number of the compounds of formula I showed a marked A_(2a) affinitywith Ki ranging from 1 to 10 nM. The A_(2a) selectivity for somecompounds is 200-800fold, which is markedly higher than that of thecompounds known up to now.

In the platelet aggregation test, said compounds proved to effectivelyblock the antiaggregatory effects induced by A_(2a) agonists, with pA₂values ranging from 8 to 10.

The compounds of the invention antagonize in a variety of vasculardistricts, with a similar potency, vasodilatation mediated by A_(2a)receptors, whereas they are not able of blocking the negativechronotropic effect induced by A₁ agonists in rat isolated atria. In thein vivo models, the tested compounds showed a poor stimulating activityon central nervous system, they antagonized the hypotension induced byA_(2a) agonists without changing significantly the heart rate. Thecompounds turned out to be active at doses from 0.001 to 3 mg/kgintraperitoneally.

For the envisaged therapeutical uses, compounds I will be formulated assuitable pharmaceutical compositions, which can be administered, forexample, by the oral, parenteral or transdermal routes, using knowntechniques and excipients, as described for example in Remington'sPharmaceutical Sciences Handbook, Mack Pub. Co., NY, USA, XVII ed. Saidcompositions are comprised within the scope of the present invention.

The daily dosage will depend, of course, on many factors (severity ofthe pathology to treat, patient conditions, toxicology andpharmacokinetic of the selected compound) but generally it will rangefrom 0.01 to 10 mg/kg body weight, preferably from 0.1 to 1 mg/kg,optionally subdivided in more administrations. Examples ofpharmaceutical compositions comprise capsules, tablets, solutions,syrups, vials, controlled-release forms, transdermal forms (patches) andthe like.

The following examples further illustrate the invention.

EXAMPLE 1 5-amino-7- β-(4-hydroxy)-phenylethyl!-2-(furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine

A solution of 5-amino-7-β-(4-benzyloxy)-phenylethyl!-2-(2-furyl)-pyrazolo 4,3-e!-1,2,4-triazolo-1,5-c!pyrimidine (1.5 g; 0.003 moles) in THF (20 ml) is added withHCOONH₄ (0.81 g, 0.012 moles) and 10% C-Pd (0.3 g) and refluxed for 2hours. When the reaction is complete, the catalyst is filtered off andthe supernatant is concentrated. The residue is chromatographed (AcOEt)to give 0.44 (41%) of the desired compound, which is a white solid, m.p.265 (dec.). IR (KBr) cm⁻¹ : 3500-3100. 1650. 1610. 1525, 1435; ¹ H NMR(DMSO) δ: 3.04, (t, 2H, J=8 Hz); 4.41 (t, 2H, J=8 Hz); 6.60 (d, 2H, J=8Hz); 6.73-6.74 (m, 1H); 6.93 (d, 2H, J=8); 7.22 (d, 1H, J=4 Hz); 7.94(s, 1H); 8.07 (bs, 2H); 8.16 (s, 1H), 9.22 (s, 1H).

EXAMPLE 2

0.25 ml of an 1M BCl₃ solution in CH₂ Cl₂ were added at 0° C. to asolution of 50 mg (0.12 mmol) of 5-amino-7β-(3,4-methylenedioxy)phenylethyl!-2-(2-furyl)-pyrazole-4,3-e!-1,2,4-triazole- 1,5-c!-pyrimidine.

The mixture was left at 4° C. for 5 h. 1 ml of methanol was added andthe solvent was evaporated, to give 33 mg of the corresponding3,4-dihydroxy derivative (m.p. 272° dec.).

EXAMPLE 3

Following the same procedures of Example 1 or 2, starting from thesuitable benzyloxy- or methylendioxy-substituted precursors, thefollowing compounds were obtained:

5-amino-7- β-(4-hydroxy-3-methoxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-7- β-(3-hydroxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-7- β-(2-hydroxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-7- γ-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-pyrazolo4,3-e!1,2,4-triazolo 1,5-c!pyrimidine;

m.p 189-191° C.;

5-amino-7- 4-hydroxybenzyl!-2-(2-furyl)-pyrazolo 4,3-e!-1,2,4-triazolo1,5-c!pyrimidine, m.p.>280° C.;

5-amino-8- β-(4-hydroxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-8- γ-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-8- β-(3,4-dihydroxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-8- β-(3,4-methylenedioxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine;

5-amino-8-(4-hydroxybenzyl)-2-(2-furyl)-pyrazolo 4,3-e!-1,2,4-triazolo1,5-c!pyrimidine;

5-amino-7- β-(4-hydroxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-7- β-(4-hydroxy-3-iodo)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-7- γ-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-7- γ-(3,4-dihydroxy)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; m.p.204-206° C.;

5-amino-7-γ-(3,4-methylendioxy)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; m.p 210-211° C.;

5-amino-7- γ-(4-hydroxy-3-iodo)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-7- β-(3,4-dihydroxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-7-β-(3,4-methylenedioxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-8- β-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-8- γ-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-8- β-(3,4-dihydroxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-8-β-(3,4-methylenedioxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-7- β-(4-hydroxy-3-iodo)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-7- γ-(4-hydroxy-3-iodo)-phenylpropyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!-pyrimidine;

5-amino-7- β-(3,4-methylenedioxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!-pyrimidine.

We claim:
 1. Compounds of general formula (I) ##STR8## wherein: A is apyrazole, imidazole or triazole ring ##STR9## R₁ and R₂, which are thesame or different, are H, OH, halogen, C₁ -C₄ alkoxy, C₁ -C₄ alkyl,nitro, amino, cyano, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, carboxy,carboxamido groups; moreover the OH group, together with one of R₁ orR₂, or R₁ and R₂, can form the methylenedioxy group --O--CH₂ --O--;n isan integer from 0 to 4,or the pharmaceutically acceptable salts thereof.2. Compounds according to claim 1, wherein A is a group selected from##STR10##
 3. Compounds according to claim 1, wherein A is pyrazolo, n isfrom 1 to 4, the OH group on the phenyl ring is at the para position andR₁ and R₂ are hydrogen.
 4. Compounds according to claim 1, wherein A ispyrazolo, n is from 1 to 4, the OH group on the phenyl ring is at themeta position and R₁ and R₂ are hydrogen.
 5. Compounds according toclaim 1, wherein A is pyrazolo, n is from 1 to 4, the OH group on thephenyl ring is at the para position, R₁ is methoxy, preferably at themeta position, R₂ is hydrogen.
 6. Compounds according to claim 1,wherein A is pyrazolo, n is from 1 to 4, the OH group on the phenyl ringis at the para position, R₁ is hydroxy, preferably at the meta position,R₂ is hydrogen.
 7. Compounds according to claim 1, wherein A is1,2,3-triazolo, n is from 1 to 4, and the OH group on the phenyl ringcan be at all the possible positions.
 8. A compound according to claim1, selected from the group consisting of: 5-amino-7-β-(4-hydroxy-3-methoxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo1,5-c!pyrimidine;5-amino-7-β-(3-hydroxy)-phenylethyl!-2-(2-furyl)-pyrazolo 4,3-e!-1,2,4-triazolo1,5-c!pyrimidine; 5-amino-7-β-(2-hydroxy)-phenylethyl!-2-(2-furyl)-pyrazolo 4,3-e!-1,2,4-triazolo1,5-c!pyrimidine; 5-amino-7-γ-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-pyrazolo 4,3-e!1,2,4-triazolo1,5-c!pyrimidine; 5-amino-7- 4-hydroxybenzyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine; 5-amino-8-β-(4-hydroxy)-phenylethyl!-2-(2-furyl)-pyrazolo 4,3-e!-1,2,4-triazolo1,5-c!pyrimidine; 5-amino-8-γ-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-pyrazolo 4,3-e!-1,2,4-triazolo1,5-c!pyrimidine; 5-amino-8-β-(3,4-dihydroxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-8-β-(3,4-methylenedioxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!pyrimidine;5-amino-8-(4-hydroxybenzyl)-2-(2-furyl)-pyrazolo 4,3-e!-1,2,4-triazolo1,5-c!pyrimidine; 5-amino-7-β-(4-hydroxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-7-β-(4-hydroxy-3-iodo)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-7-γ-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-7-γ-(3,4-dihydroxy)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-7-γ-(3,4-methylendioxy)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; m.p 210-211° C.; 5-amino-7-γ-(4-hydroxy-3-iodo)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-7-β-(3,4-dihydroxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-7-β-(3,4-methylenedioxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-8-β-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-8-γ-(4-hydroxy)-phenylpropyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-8-β-(3,4-dihydroxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-8-β-(3,4-methylenedioxy)-phenylethyl!-2-(2-furyl)-1,2,3-triazolo5,4-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-7-β-(4-hydroxy-3-iodo)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-7-γ-(4-hydroxy-3-iodo)-phenylpropyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!-pyrimidine; 5-amino-7-β-(3,4-methylenedioxy)-phenylethyl!-2-(2-furyl)-pyrazolo4,3-e!-1,2,4-triazolo 1,5-c!-pyrimidine.
 9. Pharmaceutical compositionscontaining as the active ingredient a therapeutically effective amountof a compound of the claim 1 in admixture with conventional carriers andexcipients.